The proposed research will investigate damage to the olfactory system caused by unilateral naris closure. The Preliminary Studies provide the first documentation that unilateral naris closure places an animal in double jeopardy by inducing dramatic losses of olfactory receptor neurons in the rostral 1/3 of the open-side olfactory epithelium and causing the olfactory bulbs on the closed or sensory-deprived side to atrophy an average of 19.5%. These findings and the proposed studies should provide important new knowledge about the basic physiology and life cycle of olfactory receptor neurons and their trophic effects on the olfactory bulbs. They further point the way to development of sorely needed clini- cal interventions that could prevent or ameliorate some types of human olfactory dysfunction. Six experiments are proposed for the next 4 years to implement the objectives of this application. The specific aims of these are to determine: 1) if receptor neuron losses on the open side become progressively greater with time; 2) if reopening a closed naris can reverse damage to the olfactory epithelium on the open side and damage to the olfactory bulb on the closed side; 3) if turnover rates vary with the different rates of loss of receptor neurons on the 2 sides; 4) the effects on the olfactory epithelia of housing naris closure mice in ambient condi- tions of high humidity versus low humidity; 5) the effects on the olfactory epithelia of housing naris closure and normal mice in disease-free versus disease-present conditions; and 6) if long-term experimental inhibition of nasal cycling induces loss of olfactory receptor neurons. Naris closure and reopening will be performed by cautery, microsurgery and suture while the animal is under deep pentobarbital anesthesia. The olfactory epithelia will be evaluated quantitatively by measuring their widths and numbers of cells spanning their widths in H&E-stained paraffin sections of decalcified heads. Immunohistochemistry for olfactory marker protein will be used to further visualize differences. Turnover rates will be obtained using tritiated-thymidine on-the-slide autoradiography.